The present invention relates to a new process for the industrial synthesis of (3aS)-5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine of formula (I): 
and addition salts thereof with a pharmaceutically acceptable acid.
The compound of formula (I) and salts thereof have powerful activity facilitating the activation caused by glutamic acid at the level of the AMPA receptors, making them useful in the treatment and prevention of pathologies associated with malfunction of glutamatergic neurotransmission, such as disorders of memory and cognition associated with ageing and with syndromes of anxiety and depression, deficiencies of memory in progressive neurodegenerative diseases and also the sequelae of acute neurodegenerative diseases.
The compound of formula (I), its use in therapeutics and a preparation method have been described in patent specification EP 0 692 484.
In view of the pharmaceutical interest in this compound and of the fact that only the (S) isomer has facilitatory activity on the AMPA flux, it has been of prime importance to be able to prepare it by an effective synthesis process that allows the (S) isomer to be obtained selectively in a good yield and with excellent purity and that can be readily applied on an industrial scale.
Two methods for the preparation of the compound of formula (I) are known. However, those processes cannot be used on an industrial scale:
Patent specification EP 0 692 484 describes preparation of the compound of formula (I) by non-enantioselective reduction of 5,5-dioxo-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine using sodium borohydride, followed by separation of the resulting racemic mixture by preparative HPLC chromatography on a chiral phase.
However, this means of separation is not viable on an industrial scale because of its very low productivity.
The publication Bioorg. Med. Chem. Lett. 1996, 6, 3003 describes preparation of the compound of formula (I) by reduction of 5,5-dioxo-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine using a chiral complex of lithium aluminium hydride. However, the low enantioselectivity of the reduction necessitates laborious enrichment in order to obtain the compound of formula (I) in its optically pure form.
The Applicant has now developed a process for the industrial synthesis of the compound of formula (I) by enantioselective catalytic hydrogenation of 5,5-dioxo-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine, allowing the (S) isomer to be obtained directly in an excellent yield and with excellent chemical and enantiomeric purity.
More specifically, the present invention relates to a process for the industrial synthesis of the compound of formula (I), which process is characterised in that 5,5-dioxo-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine of formula (II): 
is hydrogenated in the presence of the catalyst (R)-BINAP RuCl2 (R,R)-DPEN of formula (III): 
in a quantity of from 0.4 to 2 mmol per mol of compound of formula (II),
in a mixture of toluene and isopropanol wherein the proportion of toluene is from 10 to 90% by volume, preferably from 70 to 80% by volume,
under hydrogen pressure of from 4 to 25 bar, preferably from 10 to 15 bar,
at a temperature of from 40 to 90xc2x0 C., preferably from 65 to 75xc2x0 C.,
and in the presence of a base such as, for example, potassium or sodium tert-butoxide dissolved in an alcoholic solvent such as, for example, tert-butanol or isopropanol, in an amount of from 0.8 to 1.5 mol per mol of compound of formula (I), preferably from 1 to 1.2 mol per mol of compound of formula (I),
to yield directly, after isolation and then recrystallisation, the compound of formula (I) having an enantiomeric excess of more than 80%.